Preparation of halogen analogs of picloram

ABSTRACT

Methods for preparing 5-fluoro-6-(bromo or chloro)picloram analogs, or derivatives thereof, from picloram acid, picloram ester, or the nitrile analog of picloram are provided. The methods include chemical process steps that: (1) introduce a phthaloyl group onto the 4-amino substituent of picloram acid, picloram ester, or the nitrile analog of picloram, (2) add 2 fluorine atoms at the 5,6-positions of the pyridine ring using halex fluorination chemistry, (3) remove the phthaloyl group, hydrolyze the ester or nitrile substituent, and add chlorine or bromine to the 6-position by treatment with an acid and water, and finally, (4) esterify the 5-fluoro-6-(bromo or chloro)picloram acid produced in step (3) to a 5-fluoro-6-(bromo or chloro)picloram ester.

PRIORITY

This application claims priority to U.S. 62/733,285 filed Sep. 19, 2018which is hereby incorporated herein by reference in its entirety.

BACKGROUND

Picloram (I; X, Y=Cl), a member of the picolinic acid family ofherbicides, is an auxin herbicide that offers very good control ofbroadleaf weeds in rangeland, grass pastures, forestry and industrialsettings (12^(th) Edition of the Pesticide Manual, 2000). Picloram hasalso served as a raw material for the production of another useful auxinherbicide known as aminopyralid (I, X=Cl, Y=H).

SUMMARY

Described herein are methods for preparing 5,6-dihalo analogs ofpicloram from picloram or derivatives (esters or the nitrile) thereof.Specifically, 5-fluoro-6-(bromo or chloro)picloram analogs, orderivatives (esters or the nitrile) thereof, of Formula II may beprepared.

-   -   wherein X=Cl or Br, Z is COOR or CN, and R is C₁-C₁₂ alkyl,        C₆-C₁₂ arylalkyl, C₃-C₁₂ alkynyl, C₁-C₃ alkyl substituted with        CN, or H.

Compounds of Formula II are useful intermediates employed in thesynthesis of herbicides as described in WO 2012/103044 A1 and WO2012/103041 A2.

The methods involve first combining a compound of Formula III with aphthaloyl halide of Formula Ma or a phthalic anhydride of Formula IIIb,and, optionally a base,

wherein each Y substituent is independently selected from H, F, Cl, Br,I, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, ornitro, wherein n is 1, 2, 3, or 4; and W is Cl or Br. Then isolating acompound of Formula IV from the first step

and combining the isolated compound of Formula IV with a fluorinatingcompound or a fluorinating mixture of compounds. Next a compound ofFormula V

is isolated and combined with HCl or HBr and water. Finally, a compoundof Formula II is isolated.

Another aspect of the present disclosure are the novel compoundsproduced by the described methods, viz., the compounds:

wherein X=Cl or Br, Z is COOR, and R is C₂-C₁₂ alkyl, C₆-C₁₂ arylalkyl,C₃-C₁₂ alkynyl, C₁-C₃ alkyl substituted with CN, or H; and

wherein Z is COOR or CN, and R is H, C₁-C₁₂ alkyl, or C₆-C₁₂ arylalkyl;and each Y substituent is independently selected from H, F, Cl, Br, I,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or nitro,wherein n is 1, 2, 3, or 4.

DETAILED DESCRIPTION

A method for preparing 5-fluoro-6-(bromo or chloro)picloram analogs, orderivatives thereof, of Formula II from a Picloram ester or nitrile ofFormula III is provided. As illustrated in Scheme 1, the method includeschemical process steps that: (1) introduce a cyclic imide group, such asphthaloyl, to the 4-amino substituent by reaction of the compound ofFormula III with a diacid halide, such as phthaloyl chloride, or an acidanhydride, such as phthalic anhydride, (2) place 2 fluorine atoms at the5,6-positions of the pyridine ring by use of fluorination chemistry, and(3) remove the cyclic imide group, hydrolyze the ester or nitrilesubstituent, and introduce a halogen atom at the 6-position by treatmentwith an acid HX and water, wherein X is Cl or Br.

wherein X is Cl or Br, Z is COOR or CN, R is C₁-C₁₂ alkyl, and R¹ isC₂-C₁₂ alkyl, C₆-C₁₂ arylalkyl, C₃-C₁₂ alkynyl, or C₁-C₃ alkylsubstituted with CN.

I. Definitions

The compound of Formula IV, wherein Z is CO₂R or CN, R is a C₁-C₁₂ alkylor C₆-C₁₂ arylalkyl, and each Y substituent is independently selectedfrom H, F, Cl, Br, I, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, or nitro, wherein n is 1, 2, 3, 4, 5, 6, 7, or 8 may berepresented by the following chemical structures. The phthaloylstructures may be represented by either of the two versions of thephthaloyl structure which are considered to be identical in allrespects.

An aspect of the invention is a compound of formula IV wherein Z is CO₂Ror CN, R is a C₁-C₁₂ alkyl or C₆-C₁₂ arylalkyl, and each Y substituentis independently selected from H, F, Cl, Br, I, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or nitro, wherein n is 1, 2,3, or 4.

An aspect of the invention is a compound of formula IVa wherein Z isCO₂R or CN, R is a C₁-C₁₂ alkyl or C₆-C₁₂ arylalkyl.

An aspect of the invention is a compound of formula IVb wherein Z isCO₂R or CN, R is a C₁-C₁₂ alkyl or C₆-C₁₂ arylalkyl, and each Ysubstituent is independently selected from H, F, Cl, Br, I, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or nitro, wherein n is1, or 2.

An aspect of the invention is a compound of formula IVc wherein Z isCO₂R or CN, R is a C₁-C₁₂ alkyl or C₆-C₁₂ arylalkyl, and each Ysubstituent is independently selected from H, F, Cl, Br, I, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or nitro, wherein n is1, 2, 3, 4, 5, or 6.

An aspect of the invention is a compound of formula IVd wherein Z isCO₂R or CN, R is a C₁-C₁₂ alkyl or C₆-C₁₂ arylalkyl, and each Ysubstituent is independently selected from H, F, Cl, Br, I, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or nitro, wherein n is1, 2, 3, 4, 5, 6, 7, or 8.

An aspect of the invention is a compound of formula IVe wherein Z isCO₂R or CN, R is a C₁-C₁₂ alkyl or C₆-C₁₂ arylalkyl.

An aspect of the invention is a compound of formula IVf wherein Z isCO₂R or CN, R is a C₁-C₁₂ alkyl or C₆-C₁₂ arylalkyl, and each Ysubstituent is independently selected from H, F, Cl, Br, I, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or nitro, wherein n is1, 2, 3, or 4 and wherein 2 Y groups may be bonded to one another toform a ring.

An aspect of the invention is a compound of formula IVg wherein Z isCO₂R or CN, R is a C₁-C₁₂ alkyl or C₆-C₁₂ arylalkyl, and each Ysubstituent is independently selected from H, F, Cl, Br, I, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or nitro, wherein n is1, 2, 3, 4, 5, or 6.

An aspect of the invention is a compound of formula IVh wherein Z isCO₂R or CN, R is a C₁-C₁₂ alkyl or C₆-C₁₂ arylalkyl, and each Ysubstituent is independently selected from H, F, Cl, Br, I, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or nitro, wherein n is1, 2, 3, 4, 5, 6, 7, or 8.

As used herein, the term “aryl,” as well as derivative terms such asaryloxy, refers to groups that include a monovalent aromatic carbocyclicgroup of from 6 to 14 carbon atoms. Aryl groups can include a singlering or multiple condensed rings. In some embodiments, aryl groupsinclude C₆-C₁₀ aryl groups. Examples of aryl groups include, but are notlimited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl,phenylcyclopropyl, and indanyl. In some embodiments, the aryl group canbe a phenyl, indanyl or naphthyl group. The term “heteroaryl”, as wellas derivative terms such as “heteroaryloxy”, refers to a 5- or6-membered aromatic ring containing one or more heteroatoms, viz., N, Oor S; these heteroaromatic rings may be fused to other aromatic systems.In some embodiments, the heteroaryl group can be a pyridyl, pyrimidyl ora triazinyl group. The aryl or heteroaryl groups may be unsubstituted orsubstituted with one or more chemical moieties. Examples of suitablesubstituents include, for example, amino, halo, hydroxy, nitro, cyano,formyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ acyl, C₁-C₆ alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ alkyl sulfonyl, C₁-C₁₀ alkoxycarbonyl, C₁-C₆carbamoyl, hydroxycarbonyl, C₁-C₆ alkylcarbonyl, aminocarbonyl, C₁-C₆alkylaminocarbonyl, C₁-C₆ dialkylaminocarbonyl, provided that thesubstituents are sterically compatible and the rules of chemical bondingand strain energy are satisfied. Preferred substituents include halogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and nitro.

As used herein, the term “alkyl,” refers to linear alkyl, branchedalkyl, or cyclic alkyl groups. Cyclic alkyl groups may also includethose groups referred to as cycloalkyl or alicyclic groups such as, forexample, cyclohexyl or cyclopentyl.

As used herein, the term “C₆-C₁₂ arylalkyl,” also includes the benzylgroup (i.e., CH₂Ph).

II. Preparation of Phthalimide IV

The first step of the method to prepare the compound of Formula II isshown in Scheme 3 and involves the conversion of the compound of FormulaIII, wherein Z is CO₂R or CN, and R is a C₁-C₁₂ alkyl or C₆-C₁₂arylalkyl, to the corresponding cyclic imide of Formula IV by reactionof III with a diacid halide, such as phthaloyl halide of Formula Ma oran acid anhydride, such as phthalic anhydride of Formula IIIb, wherein Xis Cl or Br, and each Y substituent is independently selected from H, F,Cl, Br, I, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,or nitro, wherein n is 1, 2, 3, or 4.

The process step to make IV can be conducted in solvents such as, butnot limited to, polar aprotic solvents like acetonitrile (ACN), toluene,dimethylformamide (DMF), propionitrile, or benzonitrile, ethers such asTHF, 2-methyl-THF, dioxane, cyclopentyl methyl ether (CPME),monoethyleneglycol ethers, diethyleneglycol ethers, monopropyleneglycolethers or dipropyleneglycol ethers, or ketones such as methyl isobutylketone (MIBK), and mixtures thereof. The temperature range forconducting this process step may range from about 25° C. to about 100°C., from about 25° C. to about 90° C., from about 25° C. to about 80°C., from about 25° C. to about 70° C., from about 25° C. to about 60°C., or from about 25° C. to about 55° C., and the reaction may beconducted over a time period ranging from about 1 hour to about 72hours, from about 1 hour to about 48 hours, from about 1 hour to about24 hours, from about 1 hour to about 12 hours, from about 1 hour toabout 6 hours, from about 2 hours to about 24 hours, from about 4 hoursto about 24 hours, from about 2 hours to about 12 hours, or from about 4hour to about 12 hours.

From about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about1 to about 1.5, about 1 to about 1.4, about 1 to about 1.3, about 1 toabout 1.2, or from about 1 to about 1.1 molar equivalents of thephthaloyl halide or the phthalic anyhdride can be used in the process. Abase can be used to capture the HX acid liberated in the process whenusing a phthaloyl halide and may be selected from bases liketrialkylamines such as, but not limited to, trimethylamine,triethylamine, or tripropylamine, and nitrogen containing heterocyclessuch as pyridine, and alkyl substituted pyridines such as 2-picoline or3-picoline. Phthalimide IV can be isolated from the process by employingstandard isolation and purification techniques. A base can be optionallyused with the phthalic anhydride in the process to make IV.

In one embodiment, the use of an acylation catalyst such as, but notlimited to, DMAP (4-(dimethylamino)-pyridine) or N-methylimidazole, maybe used in the preparation of IV from IIIa or IIIb.

In another embodiment of the first step of the method to prepare thecompound of Formula II as shown in Scheme 3, the first step may bepreceded by a step whereby a carboxylic acid of Formula III, wherein Zis CO₂H, is contacted with an alcohol ROH, wherein R is a C₁-C₁₂ alkylor C₆-C₁₂ arylalkyl, in the presence of an acid or acid-forming compoundto provide the ester of Formula III, wherein Z is CO₂R. The esterproduced in this manner can then be used to prepare the phthalimide ofFormula IV as described herein.

III. Preparation of Difluorophthalimide V

The second step of the method to prepare the compound of Formula IIinvolves the conversion of the compound of Formula IV, wherein Z=CO₂R orCN, R is a C₁-C₁₂ alkyl or C₆-C₁₂ arylalkyl, and each Y substituent isindependently selected from H, F, Cl, Br, I, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or nitro, wherein n is 1, 2, 3, or 4,to the corresponding difluorophthalimide of Formula V by treatment of IVwith a fluorinating compound or a fluorinating mixture of compounds inthe presence of a solvent as shown in Scheme 4.

The fluorinating compound or fluorinating mixture of compounds for usein the second step of the method may be selected from the groupincluding KF (potassium fluoride), CsF (cesium fluoride), and TMAF(tetramethylammonium fluoride), and mixtures thereof, or a mixture oftetramethylammonium chloride (TMAC) with KF or CsF.

The amount of the fluorinating compound or the fluorinating mixture ofcompounds used relative to the substrate of Formula IV to prepare thecompound of Formula V may range from about 2 to about 8 molarequivalents of KF, from about 2 to about 8 molar equivalents of CsF, orfrom about 2 to about 6 molar equivalents of TMAF. In one embodiment thefluorinating mixture of compounds includes from about 2 to about 10molar equivalents of KF or CsF and from about 0.01 to about 2.0 molarequivalents of TMAC.

Solvents that may be suitable for use with the fluorinating compounds orthe fluorinating mixture of compounds to prepare V include, but are notlimited to, polar aprotic solvents such as acetonitrile (ACN),propionitrile (PCN), benzonitrile (BCN), dimethylsulfoxide (DMSO),N,N-dimethylformamide (DMF), sulfolane, dimethylacetamide (DMAC),1,1-dimethyl-2-imidizolidinone (DMI), N,N′-dimethylpropyleneurea (DMP),N-methylpyrrolidinone (NMP), tetrahydrofuran (THF), 2-methyl-THF,dioxane, monoethyleneglycol ethers, diethyleneglycol ethers,monopropyleneglycol ethers, or dipropyleneglycol ethers, and mixturesthereof.

In one embodiment, the fluorination of IV may be conducted with KF orCsF in DMF solvent. In another embodiment, the fluorination of IV may beconducted with KF or CsF in DMSO solvent. In another embodiment, thefluorination of IV may be conducted with KF or CsF, and TMAC in DMFsolvent. In another embodiment, the fluorination of IV may be conductedwith KF or CsF, and TMAC in DMSO solvent. In another embodiment, thefluorination of IV may be conducted with TMAF in THF solvent.

It is generally preferred to conduct the fluorination of IV to prepare Vunder anhydrous or near-anhydrous conditions. These anhydrous ornear-anhydrous conditions may be obtained by prior drying of thereactants and solvents. One way to dry the reactants and/or solvents isby removal by distillation of a portion of the solvent prior toconducting the fluorination reaction.

The fluorination reaction to produce the compound of Formula V may beconducted at a temperature of at least about 0° C., at least about 10°C., at least about 20° C., at least about 25° C., at least about 30° C.,at least about 40° C., at least about 50° C., at least about 60° C., atleast about 70° C., at least about 80° C., at least about 90° C., or atleast about 100° C. The fluorination reaction to produce the compound ofFormula V may be conducted at a temperature of about 0° C. to about 50°C., from about 10° C. to about 50° C., from about 25° C. to about 50°C., from about 15° C. to about 150° C., from about 25° C. to about 150°C., from about 35° C. to about 125° C., from about 45° C. to about 115°C., from about 55° C. to about 110° C., from about 65° C. to about 110°C., from about 75° C. to about 110° C., from about 85° C. to about 110°C., from about 90° C. to about 110° C., from about 50° C. to about 100°C., from about 60° C. to about 100° C., from about 70° C. to about 100°C., from about 25° C. to about 90° C., from about 25° C. to about 80°C., about 25° C. and about 110° C., from about 25° C. to about 70° C.,or from about 25° C. to about 60° C.

Isolation of the compound of Formula V from the fluorination reactionmixture may be conducted by removing the insoluble salts by filtrationand then adding water to the resulting filtrate to precipitate thedesired product, which may be purified by employing standardpurification techniques.

IV. Preparation of 4-Amino-3-chloro-6-(chloro orbromo)-5-fluoropicolinic acid II

The next step of the method to prepare the compound of Formula IIinvolves the conversion of the compound of Formula V, wherein Z is CO₂Ror CN, R is a C₁-C₁₂ alkyl or C₆-C₁₂ arylalkyl, and each Y substituentis independently selected from H, F, Cl, Br, I, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or nitro, wherein n is 1, 2,3, or 4, to the compound of Formula II wherein X is Cl or Br. Thisconversion is shown in Scheme 5 and involves treating compound V with ahydrohalide acid HX and water, wherein X is Cl or Br, to provide thecompound of Formula II, wherein X is Cl or Br.

The conversion involves halide exchange of the 6-fluoro substituent bythe HX acid to provide either a 6-chloro or 6-bromo substituent,hydrolysis of the Z substituent to a carboxylic acid, and removal of thephthaloyl group by hydrolysis to regenerate the 4-amino substituent. Aco-solvent of acetic acid (HOAc) is useful to help facilitate thisconversion. The HX salt of compound II (wherein X is Cl or Br) may alsoform in this reaction.

This step may be conducted in two stages, wherein the first stage isconducted at lower temperature and/or with no or limited amounts ofwater to achieve halide exchange of the 6-fluoro substituent, and thesecond stage is conducted at higher temperature and/or with more waterto achieve hydrolysis of the phthaloyl group and the ester (or cyano)substituent).

In some examples, the amount of water included in this step relative tothe starting compound of Formula V on a molar basis may range from about1 to about 30, from about 1 to about 20, from about 1 to about 10, fromabout 1 to about 8, from about 1 to about 6, from about 1 to about 4,from about 2 to about 5, from about 2 to about 4, or from about 3 toabout 4 molar equivalents of water per mole of compound V.

In other examples, the amount of acid HCl or HBr included in this steprelative to the starting compound of Formula V on a molar basis mayrange from about 50 to about 1, from about 40 to about 1, from about 30to about 1, from about 20 to about 1, from about 10 to about 1, fromabout 8 to about 1, from about 6 to about 1, from about 3 to about 1,from about 2 to about 1, or from about 3 to about 2 molar equivalents ofHCl or HBr per mole of compound V.

In further examples, the reaction to produce the compound of Formula IIfrom the compound of Formula V may be conducted at a temperature fromabout 50° C. to about 150° C., from about 60° C. to about 140° C., fromabout 70° C. to about 130° C., from about 80° C. to about 120° C., fromabout 90° C. to about 120° C., or from about 100° C. to about 120° C.

A by-product of the reaction to produce the product of Formula II fromthe compound of Formula V is phthalic acid or a substituted phthalicacid, which is derived from hydrolytic cleavage of the phthaloyl groupof compound V. Methods of separating or removing the phthalic acid orthe substituted phthalic acid from the reaction mixture containing thecompound of Formula II may include, but are not limited to, solventextraction with an organic, an aqueous, or an organic-aqueous solvent,or differential aqueous solubility at certain pH levels or ranges.

In another example of this process step, the HBr or HCl salt of compoundII (wherein X is Cl or Br) may be formed in small amounts and be presentin the isolated product of Formula II. This compound (IIa) may bereduced or removed from product II by solvent extractions of crudeproduct II with water or with alcohol-water mixtures such asmethanol-water.

V. Preparation of esters of 4-Amino-3-chloro-6-(chloro orbromo)-5-fluoropicolinic acid

The acid of Formula II, wherein X is Cl or Br, may be converted into theester of Formula VI, wherein X is Cl or Br, and R¹ is C₁-C₁₂ alkyl,C₆-C₁₂ arylalkyl, C₃-C₁₂ alkynyl or C₁-C₃ alkyl substituted with CN.Methods to prepare ester VI from acid II include, but are not limitedto,

acid catalyzed esterification of acid II with an alcohol, and alkylationof acid II with an alkyl or benzyl halide under basic conditions.

VI. Isolation/Purification

After preparation of the compound of Formula II by the process describedherein, the product may be isolated by employing standard isolation andpurification techniques. For example, the crude product may be isolatedusing standard methods as described herein and purified bycrystallization or recrystallization using a single solvent or a mixtureof two or more solvents. Also, the crude product may be purified bywashing it with or stirring it in a one, two or three-component solventmixture. In one embodiment, the crude product may be purified bystirring it in an aqueous alcohol solvent mixture which can also bedescribed as an aqueous alcohol slurry treatment.

The crude product of Formula II may also be purified by dissolving it inone solvent to form a solution and then adding a second solvent to thesolution to cause the product of Formula II to crystallize out of themixture of the two solvents.

The following examples are presented to illustrate the methods andcompositions described herein.

EXAMPLES Example 1a. Preparation of methyl4-amino-3,5,6-trichloropicolinate

Picloram (100 g, 95% purity, 414 mmol, 1.0 eq.) was suspended inmethanol (800 mL). Sulfuric acid (26 mL, 487 mmol, 1.2 eq.) was added atroom temperature slowly. The reaction mixture was stirred at 75° C. (oilbath with condenser) for 2 days. The mixture was cooled down to roomtemperature. Water (200 mL) was added. The light brown solution wasconcentrated to remove methanol. The resulting residue was dissolved inwater (200 mL) and EtOAc (600 mL), cooled with ice-bath and neutralizedwith 4N NaOH and sat. NaHCO₃ solution to pH=8. EtOAc layer was separatedand aqueous layer was washed with EtOAc. Combined organic layer wasdried and concentrated to yield compound 2 (71 g, 67% yield) as paleyellow solid. HPLC purity: 99.9%. Mp. 125.8-126.1° C.; ¹H NMR (CDCl₃) δ5.38 (br s, 2H), 3.97 (s, 3H).

Example 1b. Preparation of iso-propyl 4-amino-3,5,6-trichloropicolinate

Picloram (4.66 g, 95%, 18.3 mmol, 1 eq.) was suspended in isopropylalcohol (30 mL). Concentrated sulfuric acid (0.6 g, 6.1 mmol, 0.33 eq.)was added at room temperature. The reaction mixture was then heated atreflux for 18 hr. The reaction was then cooled to room temperature. 23%Aqueous K₂CO₃ (10 mL) was slowly added to the reaction mixture, and themixture was stirred for 30 min. The reaction mixture was extracted withEtOAc (20 mL) and the organic phase was washed with 20 mL of saturated,aqueous brine. The organic phase was dried, the solvent was evaporated,and the residual solid was dried in the vacuum oven to give an off-whitesolid (4.9 g, 94%; HPLC purity: 96%). Mp 128.5-131.0° C.; ¹H-NMR (400MHz, CDCl₃): δ 5.35 (br s, 2H), 5.29 (septuplet, J=6.4 Hz, 1H), 1.39 (d,J=6.4 Hz, 6H) ppm.

Example 2a. Preparation of Phthalimide IV (Z=CO₂Me)

Compound III (Z=CO₂Me; 86 g, 337 mmol) was dissolved in acetonitrile(600 mL). Triethylamine (TEA, 94 mL, 673 mmol, 2.0 eq.) was then addedat room temperature, followed by dropwise addition of phthaloyl chloride(65 mL, 404 mmol, 1.2 eq.). The reaction mixture was stirred at 50° C.overnight. Water (100 mL) was added to the mixture. The suspension wasstirred for 1 h and filtered through filter paper. The solid was washedwith water, and then hexane, and dried. The dry solid was suspended intoluene (200 mL) and the resulting mixture was concentrated to providecompound IV (85.1 g, 66% yield) as a pale yellow solid. HPLC purity:97.7%. Mp. 185.3-185.9° C.; ¹H NMR (CDCl₃) δ 8.02 (m, 2H), 7.88 (d, 2H,m), 4.02 (s, 3H).

Example 2b. Preparation of Phthalimide IV (Z=CN)

Compound III (Z=CN; 64.06 g, 288.0 mmol) was suspended in acetonitrile(960 mL). TEA (90.0 mL, 640.0 mmol, 2.2 eq.) and DMAP (3.52 g, 28.8mmol, 0.1 eq.) were added at room temperature, followed by slow additionof phthaloyl chloride 2 (51.2 mL, 320 mmol, 1.1 eq.), maintaininginternal temperature of the reaction less than 50° C. during theaddition. The reaction mixture was stirred at room temperature for 4 h.Water (130 mL) was added to the reaction, the suspension was stirred for30 min and filtered. The solid collected was washed with water (4×150mL), hexane (2×100 mL) and dried to yield compound IV (Z=CN; 97.0 g, 96%yield) as a light purple solid, which was dissolved in dichloromethane(DCM) and passed through a silica gel pad to give an off-white solidwith an HPLC purity: 99.6%. Mp. 233.7-234.8° C.; ¹HNMR (400 mHz,DMSO-d₆): δ 8.14 (2H, m), 8.04 (2H, m).

Example 2c. Preparation of Phthalimide IV (Z=CO₂Me)

Picloram (105.25 g, 414.9 mmol, 95.2% purity, 1.0 eq.) was suspended inMeOH (650 mL) in a 3 L 3-neck flask equipped with mechanical stirrer andcondenser. The mixture was vigorously stirred at room temperature.Thionyl chloride (0.90 mL, 12 mmol, 0.03 eq.) was added dropwise. Thereaction mixture was stirred at 75° C. (external temperature) for 18hours. The white suspension changed to light yellow clear solution afterreaction. A sample was taken for HPLC analysis (96.7% methyl ester, 2.3%Picloram). After partially removing methanol to about 150 mL remaining,500 mL toluene was added and co-evaporated at 40-55° C. under housevacuum to dryness. A sample was taken for ¹H-NMR analysis and no MeOH ortoluene remained. Then, 690 mL MeCN was added to form a turbid solution.To this solution TEA (134 mL, 959.0 mmol, 2.3 eq.) and DMAP (5.33 g,43.6 mmol, 0.105 eq.) were added, followed by dropwise addition ofphthaloyl chloride (77 mL, 479.5 mmol, 90% purity, 1.15 eq) to providean orange reaction mixture (exothermic). At this step, the temperaturewas controlled below 55° C. by adjusting the addition rate. Afteraddition was complete, the reaction mixture was stirred for another 2hours. Water (200 mL) was then added to the mixture. The resultingsuspension was stirred for 30 min and filtered. The wet cake collectedon the funnel was washed with water (2×200 mL), hexanes (200 mL) anddried under vacuum to yield IV (154.4 g, 96% yield over 2 steps, HPLCpurity: 98%) as a beige solid.

Example 2d. Preparation of Phthalimide IV (Z=CO₂iPr)

Step 1: A 3 L, 3-neck flask equipped with mechanical stirrer, condenserand addition funnel was charged with Picloram (100 g, 98.2% pure, 414. 1mmol, 1 eq.) and iPrOH (950 mL). SOCl₂ (15.1 mL, 207 mmol, 0.5 eq.) wasadded dropwise via addition funnel to the slurry at room temperature andthen the reaction mixture was heated at reflux for 24 h. The reactionmixture was cooled down to room temperature, the solvent was evaporatedto dryness and then co-evaporated with MeCN (2×100 mL) to yield a whitesolid (117.5 g crude). HPLC: 93.6% IV, 2.84% Picloram.

Step 2: A 3 L, 3-neck flask equipped with mechanical stirrer,thermometer and addition funnel was charged with the white solidisolated above, MeCN (700 mL), TEA (150 mL, 1076.7 mmol, 2.6 eq.) andDMAP (5.05 g, 41.4 mmol, 0.1 eq.). Phthaloyl chloride (90% pure, 73 mL,455.51 mmol, 1.1 eq.) was added dropwise via addition funnel to maintainthe temperature below 55° C. The reaction mixture was stirred at roomtemperature for 3 h. Water (250 mL) was added to the mixture. Theresulting suspension was stirred for 30 min and filtered through filterpaper. The solid was washed with water (3×100 mL) and hexane (2×100 mL)and dried. The solid was co-evaporated with toluene (2×250 mL), dried,washed with hexanes (2×200 mL) and dried again to yield compound IV(151.5 g, 88% yield) as a pale, yellow solid. HPLC: 98.8% purity. Mp.157.0-157.9° C.; ¹H-NMR (400 MHz, CDCl₃): δ 8.00-8.04 (m, 2H), 7.86-7.90(m, 2H), 5.33 (septuplet, J=6.4 Hz, 1H), 1.42 (d, J=6.4 Hz, 6H) ppm.

Example 2e. Preparation of Phthalimide IV (Z=CO₂iPr)

Compound III (8.1 g, 27.6 mmol, 1.0 eq.) was suspended in CH₃CN (33 mL)in a 100 mL RBF equipped with magnetic stirrer and condenser. TEA (9.6mL, 69.0 mmol, 2.5 eq.) and Phthalic anhydride (4.9 g, 33.1 mmol, 1.2eq.) were added at rt, followed by DMAP (0.34 g, 2.76 mmol, 0.1 eq.).The yellow suspension was stirred at 80° C. (oil bath temperature) for 2hours. Yellow clear solution was observed after 5 min in 80° C. oilbath. Additional Phthalic anhydride (4.0 g, 27.0 mmol, 1 eq.) was addedto the reaction mixture at 80° C. The reaction mixture was stirred at80° C. for another 4.5 h (total reaction time was 6.5 h). The reactionwas cooled to rt and water (33 mL) was added to the mixture. Thesuspension was stirred for 30 min and filtered through filter paper. Thewet solid was washed with water and hexane and dried at 55° C. in vacuumoven to yield 3 (9.8 g, 86% yield) as yellow solid. HPLC purity: 99.2%.

Example 2f. Preparation of Phthalimide IV (Z=CO₂iPr)

To a suspension of compound III (2.5 g, 8.82 mmol, 1.0 eq.) in toluene(11 mL) was added triethylamine (2.96 mL, 21.2 mmol, 2.5 eq.) andphthalic anhydride (3.26 g, 22.0 mmol, 2.5 eq.). The resultingsuspension was stirred in a 90° C. oil bath for 18 h. The clear yellowsolution was cooled gradually to room temperature to provide a thickbeige slurry. Saturated NaHCO₃ solution (5 mL) was added slowly at roomtemperature and the resulting slurry was stirred in an ice water bathfor 1 h. Solid was collected by vacuum filtration followed by water wash(2×5 mL). The wet solid was further dried in a vacuum oven at 55° C. for5 h to provide product IV (3.1 g, 86% yield; HPLC purity: 99.5%) asoff-white powdery solid.

Example 2g. Preparation of Phthalimide IV (Z=CO₂iPr)

A 2 L flask was charged with Picloram (101.8 g, 98.2% purity, 0.414 mol,1.0 eq.) and IPA (918.3 mL). SOCl₂ (15.6 mL, 97% purity, 0.21 mol, 0.5eq.) was added and the reaction mixture was heated at reflux for 17 h.Then IPA (750 mL) was distilled off under atmospheric pressure. Toluene(600 mL) was added to the resulting solution. Distillation was continuedand after another 2 h a mixture of IPA/toluene (600 mL) was distilledoff at 81˜110° C.

To the stirred suspension, TEA (144.3 mL, 1.04 mol, 2.5 eq.) was addedfollowed by Phthalic anhydride (99% purity, 153.3 g, 1.04 mol, 2.5 eq.)in portions. The reaction mixture was heated at 88˜93° C. for 17 h,cooled to room temperature. Sat. NaHCO₃ aq. (400 mL) was added slowlyover 0.5 h while cooling to keep temperature below 20° C. After additionof sat. NaHCO₃ aq was finished the resultant slurry was stirred at roomtemperature for 2 h, filtered, washed with water (3×100 mL), and driedat 60° C. for 24 h to afford product IV (144.0 g, 84.2% yield; HPLCpurity: 99.03%).

Example 3a. Preparation of Difluorophthalimide V (Z=CO₂Me)

To compound IV (Z=CO₂Me; 5.00 g, 12.97 mmol) in a 250 mL, round-bottomflask under nitrogen was added anhydrous THF (100 mL) andtetramethylammonium fluoride (TMAF; 4.83 g, 51.87 mmol, 4 eq.; Aldrich)in one portion. The reaction mixture was stirred at room temperature for5 h, cooled down to 0° C., quenched with water (400 mL) and stirred at0° C. for 1 h. The solid product present was collected by filtration,washed with water (2×100 mL), and hexanes (3×100 mL), and dried toprovide compound V (4.0 g, 87% yield) as a pale yellow solid. HPLCpurity: 92.3% of V; Mp. 180.2-182.6° C.; ¹H NMR (d₆-DMSO) δ 8.12 (d,2H), 8.02 (d, 2H), 3.94 (s, 3H). F NMR (d₆-DMSO) δ −83.30, −133.05. Alsocontained 6.6% of the 3,5,6-trifluorinated side-product.

Example 3b. Preparation of Difluorophthalimide V (Z=CO₂Me)

A mixture of CsF (82.7 g, 545 mmol) in DMSO (1.2 L) was distilled at 90°C. under in-house vacuum to remove 250 mL of DMSO. After cooling down toroom temperature with N2, compound IV (60.0 g, 156 mmol) was added inthree portion. The mixture was vigorously stirred under N2 for 27 h at25° C., and then poured into ice water (3.6 L), stirred for 1 h,filtered, and the filtered solid washed with water (600 mL) and hexanes(300 mL), and dried to provide compound V (55 g, 100% crude) as anoff-white solid. HPLC purity: 93.6% (contains 1.3% monofluoroside-product and 2.3% trifluoro side-product). The off-white solid wasrefluxed in MeOH (150 mL) for 30 min and filtered to give V (51.1 g,92.7% yield) as a pale, beige solid: HPLC purity: 95.7%. Also contained1.3% 6-monofluoro side-product and 1.7% 3,5,6-trifluoro side-product.

A sample of the pale, beige solid (Compound V, 1.0 g) was dissolved in aminimum amount of hot EtOAc (12.5 mL) and the resulting solution wasdiluted with 25 mL of methanol. The resulting solution was graduallycooled with stirring to room temperature and then was cooled in anice/water bath. The mixture that formed was filtered, and the filteredsolid was washed twice with 5 mL of MeOH and dried to yield Compound V(0.81 g, 81% recovery) as off-white, fine crystals. HPLC purity: 98.1%.Also contained 6-monofluoro side-product: 0.8% and 3,5,6-trifluoroside-product: 0.9%.

Example 3c. Preparation of Difluorophthalimide V (Z=CO₂iPr)

Solid potassium fluoride (12.7 g, 219 mmol; Sigma Aldrich) was added toa 1 L jacketed glass reactor which had been purged with nitrogen and wasmaintained with a nitrogen sweep on the headspace. The reactor wasfitted with a 1″ diameter, trayed distilling column. Then, 353.0 g ofdimethylsulfoxide (DMSO; Fischer Scientific) was added to the reactor.The mixture was agitated at a rate of 350 RPM. A vacuum of approximately40 mmHg was applied and the temperature of the reactor contents wasincreased to approximately 108° C. Approximately 100 mL of material wasdistilled with the distilling column and removed from the reactor. Thetemperature of the reactor contents were reduced to 75° C. and the watercontent was determined by Karl-Fischer analysis to be 51 ppm. Thereactor was then charged with compound IV (24.9 g, 60.2 mmol) and thetemperature was increased to 100° C. The reaction was held at 100° C.for approximately 7.5 hours. The reactor was then cooled to 75° C. andthe reaction mixture was passed through a fritted filter to remove thesolid salts. The filtered salts were washed with 44 g of DMSO and thefiltrate and wash were added to a second vessel for crystallization. Thesecond vessel was cooled to 12° C., the contents were agitated at 250RPM, and 363 g of water was continuously added to the second vessel overapproximately 2 hours. A mixture formed and was stirred for another onehour at 12° C., and the solid present was then collected by filtration,washed with about 68 g of water, and dried in a vacuum oven at 60° C.and 25 torr overnight. The resulting dry solid (21.5 g, 94% yield)provided 93.7% of the 5,6-di-F desired product (V) Mp: 115.8-117.1° C.;¹H NMR (400 MHz, CDCl₃): δ 8.00-8.06 (2H, m), 7.86-7.91 (2H, m), 5.32(1H, septet, J=6.0 Hz), 1.42 (6H, d, J=6.0 Hz). ¹⁹F NMR (376 MHz,CDCl₃): −134.21 (d), −82.76 (d). Also contained 2.6% of the3,5,6-trifluoro side-product and 2.0% of the 6-monofluoro side-product.

Example 3d. Preparation of Difluorophthalimide V (Z=CO₂iPr)

Solid potassium fluoride (7.68 g, 132 mmol; Sigma Aldrich) was added toa 1 L jacketed glass reactor which had been purged with nitrogen and wasmaintained with a nitrogen sweep on the headspace. The reactor wasfitted with a 1″ diameter, trayed distilling column containing 7 trays.Then, 211.7 g of dimethylformamide (DMF; Fischer Scientific) was addedto the reactor followed by 41.6 g of toluene (Fischer Scientific). Thesolution was agitated at a rate of 275 RPM. A vacuum of approximately350 mmHg was applied and the temperature of the reactor contents wasincreased to approximately 110° C. Approximately 75 mL of material wasdistilled with the distilling column and removed from the reactor bydecreasing the pressure as material was distilled overhead. Thetemperature of the reactor contents was then reduced to 45° C. and thewater content was determined by Karl-Fischer analysis to be 101 ppm. Thereactor was then charged with compound IV (15.2 g, 36.7 mmol) and thetemperature was increased to 100° C. The reaction was held at 100° C.for approximately 33 hours. The reactor was then cooled to 40° C. andthe reaction mixture was passed through a fritted filter to remove thesolid salts. The filtered salts were washed with 36.1 g of DMF and thefiltrate and wash were added to a second vessel for crystallization. Thesecond vessel was cooled to 10° C., the contents were agitated at 250RPM, and 170 g of water were continuously added over approximately 2hours. A mixture formed and was stirred for another 4 hours at 10° C.,and the solid present was then collected by filtration, washed withabout 44 g of water, and dried in a vacuum oven at 60° C. (25 torr)overnight. The resulting dry solid (12.0 g, 80% yield) provided 82.6% ofthe 5,6-di-F desired product (V). Also contained 1.1% of the3,5,6-trifluoro side-product and 16.6% of the 6-monofluoro side-product.

Example 3e. Preparation of Difluorophthalimide V (Z=CO₂iPr)

Solid potassium fluoride (11.15 g, 192 mmol; Sigma Aldrich) was added toa 1 L jacketed glass reactor which had been purged with nitrogen and wasmaintained with a nitrogen sweep on the headspace. The reactor wasfitted with a 1″ diameter, trayed distilling column containing 7 trays.Then, 207.2 g of dimethylsulfoxide (DMSO; Fischer Scientific) was addedto the reactor followed by solid tetramethylammonium chloride (5.29 g,48.3 mmol; TMAC, Sigma Aldrich). The mixture was agitated at a rate of350 RPM. A vacuum of approximately 100 mmHg was applied and thetemperature of the reactor contents was increased to approximately 100°C. Approximately 35 mL of material was distilled with the distillingcolumn and removed from the reactor. The temperature of the reactorcontents was then reduced to 45° C. and the water content was determinedby Karl-Fischer analysis to be 102 ppm. The reactor was then chargedwith compound IV (19.8 g, 47.9 mmol) and the temperature of the reactionmixture was increased to 60° C. The reaction was held at 60° C. forapproximately 3.5 hours and then was increased to 70° C. Thattemperature was held for approximately 8.5 hours at 70° C. and then wasincreased and held for one hour at 80° C. The reactor was then cooled to75° C. and the reaction mixture was passed through a fritted filter toremove the solid salts. The filtered salts were washed with 50 g of DMSOand the filtrate and wash were added to a second vessel forcrystallization. The second vessel was cooled to 21° C., the contentswere agitated at 250 RPM, and 267 g of water were continuously addedover approximately 2 hours. A mixture formed and was stirred for anotherone hour at 21° C., and the solid present was then collected byfiltration, washed with about 66 g of water, and dried in a vacuum ovenat 60° C. (25 torr) overnight. The resulting dry solid (15.5 g, 85%yield) provided 97.5% of the 5,6-di-F desired product (V). Alsocontained 1.7% of the 3,5,6-trifluoro side-product and 1.9% of the6-monofluoro side-product.

Example 3f. Preparation of Difluorophthalimide V (Z=CO₂iPr)

Solid potassium fluoride (12.7 g, 219 mmol; Sigma Aldrich) was added toa 1 L jacketed glass reactor which had been purged with nitrogen and wasmaintained with a nitrogen sweep on the headspace. The reactor wasfitted with a 1″ diameter, trayed distilling column containing 7 trays.Then, 408.9 g of dimethylsulfoxide (DMSO; Fischer Scientific) was addedto the reactor followed by 34.6 g (110 mmol) of a solution of 35%tetramethylammonium chloride (TMAC) in methanol (SAChem). The mixturewas agitated at a rate of 350 RPM. A vacuum of approximately 60 mmHg wasapplied and the temperature of the reactor contents was increased toapproximately 100° C. Approximately 115 mL of material was distilledwith the distilling column and removed from the reactor. The temperatureof the reactor contents was reduced to 70° C. and 54 g more DMSO wasadded to the pot before restarting the distillation and collectingapproximately 35 mL of additional distillate. The temperature of thereactor contents were reduced to 75° C. and the water content wasdetermined by Karl-Fischer analysis to be 179 ppm. The reactor was thencharged with compound IV (24.9 g, 60.2 mmol) and the temperature wasincreased to 100° C. The reaction was held at 100° C. for approximately2.25 hours. The reactor was cooled to 75° C. and the reaction mixturewas passed through a fritted filter to remove the solid salts. Thefiltered salts were washed with 116 g of DMSO and the filtrate and washwere added to a second vessel for crystallization. The second vessel wascooled to 14° C., the contents were agitated at 250 RPM, and 283 g ofwater were continuously added over approximately 2 hours. A mixtureformed and was stirred for another 1 hour at 14° C., and the solidpresent was then collected by filtration, washed with about 64 g ofwater, and dried in a vacuum oven at 60° C. (25 torr) overnight. Theresulting dry solid (22.5 g, 98% yield) provided 98.3% of the 5,6-di-Fdesired product (V). Also contained 3.8% of the 3,5,6-trifluoroside-product and 0.5% of the 6-monofluoro side-product.

Example 3g. Preparation of Difluorophthalimide V (Z=CO₂Et)

Solid potassium fluoride (5.9 g, 102 mmol; Sigma Aldrich) was added to a1 L jacketed glass reactor which had been purged with nitrogen and wasmaintained with a nitrogen sweep on the headspace. The reactor wasfitted with a 1″ diameter, trayed distilling column containing 7 trays.Then, 139.5 g of dimethylformamide (DMF; Fischer Scientific) was addedto the reactor followed by 15.8 g (50.4 mmol) of a solution of 35%tetramethylammonium chloride (TMAC) in methanol (SAChem). The solutionwas agitated at a rate of 350 RPM. A vacuum of approximately 90 mmHg wasapplied and the temperature of the reactor contents was increased toapproximately 90° C. Approximately 75 mL of material was distilled withthe distilling column and removed from the reactor. The temperature ofthe reactor contents was reduced to 45° C. and the water content wasdetermined by Karl-Fischer analysis to be 105 ppm. The reactor was thencharged with compound IV (10.05 g, 25.1 mmol) and the temperature wasincreased to 100° C. The reaction was held at 100° C. for approximately4 hours. The reactor was cooled to 50° C. and the reaction mixture waspassed through a fritted filter to remove the solid salts. The filteredsalts were washed with 73 g of DMF and the filtrate and wash were addedto a second vessel for crystallization. The second vessel was cooled to2° C., the contents were agitated at 250 RPM, and 172.3 g of water wascontinuously added to the reaction mixture over approximately 2 hours inorder to keep the temperature of the mixture below 10° C. A mixtureformed and was stirred for another 1 hour at about 10° C., and the solidpresent was then collected by filtration, washed with about 35 g ofwater, and dried in a vacuum oven at 60° C. (25 torr) overnight. Theresulting dry solid (6.44 g, 70% yield) provided 97.3% of the 5,6-di-Fdesired product (V). Mp: 111.2-116.7° C.; ¹H NMR (400 MHz, CDCl₃): δ8.00-8.04 (2H, m), 7.88-7.90 (2H, m), 4.47 (2H, q, J=6.8 Hz), 1.43 (3H,d, J=6.8 Hz); ¹⁹F NMR (376 MHz, CDCl₃): −133.57 (d), −82.54 (d). Alsocontained 2.4% of the 3,5,6-trifluoro side-product and 3.8% of the6-monofluoro side-product.

Example 3h. Preparation of Difluorophthalimide V (Z=CO₂cHexyl)

CsF (1.17 g, 7.70 mmol) was added to a 50 mL RBF equipped with stirringbar and distillation apparatus. Then 25 mL of dimethylsulfoxide (DMSO)was added. The flask was half-way merged to an oil bath. Vacuum(approximately 1 mm Hg) was connected to the distillation apparatus.Approximately 10 mL of DMSO was distilled out. Distillation apparatuswas removed and the system was cooled with N2 balloon. When oil bathreached 25° C., compound 1 (1.0 g, 2.17 mmol) was added in one portionto the flask and flask was capped with rubber stopper and nitrogenballoon. The reaction mixture was stirred at room temperature for 24 h,poured into 50 mL ice-water, stirred for 30 min and product collected.The wet cake was washed with water (2×10 mL) and hexane (10 mL) anddried in a vacuum oven at 55° C. to give V (0.89 g, 95% yield, HPLCpurity 92.9%) as a yellow solid. ¹⁹F NMR (376 MHz, DMSO-d6): δ −83.3 (d,J=26.7 Hz), −133.7 (d, J=26.7 Hz). Also contained 2.1% of the3,5,6-trifluoro side-product.

Example 3i. Preparation of Difluorophthalimide V (Z=CO₂CH₂Ph)

CsF (1.15 g, 7.58 mmol) was added to a 50 mL RBF equipped with stirringbar and distillation apparatus. Then 25 mL of dimethylsulfoxide (DMSO)was added. The flask was half-way merged to an oil bath. Vacuum(approximately 1 mm Hg) was connected to the distillation apparatus.Approximately 10 mL of DMSO was distilled out. Distillation apparatuswas removed and the system was cooled with a nitrogen balloon. CompoundIV (1.0 g, 2.17 mmol) was added in one portion. The reaction mixture wasstirred at room temperature for 24 h, poured into 50 mL ice-water,stirred for 30 min and product collected. The wet cake was washed withwater (2×10 mL) and hexane (10 mL) and dried in a vacuum oven at 55° C.to provide compound V (0.86 g, 93% yield, HPLC purity 88.4%) as a beigesolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.10-8.18 (2H, m), 8.00-8.06 (2H,m), 7.45 (2H, m), 7.30-7.42 (3H, m), 5.42 (2H, s). ¹⁹F NMR (376 MHz,DMSO-d6): δ −83.2 (d, J=26.7 Hz), −133.0 (d, J=26.7 Hz). Also contained0.7% % of the 6-monofluoro side-product and 7.6% of the 3,5,6-tri-fluoroside product.

Example 4a. Preparation of 4-Amino-3,6-dichloro-5-fluoropicolinic acid

Compound V (Z=CO₂Me; 5.0 g, 14.2 mmol) was suspended in a solution ofHCl in acetic acid (2M, 35.5 mL, 71 mmol, 5.0 eq.) in a 450 mL, sealedflask. The mixture was stirred at 110° C. (oil bath) overnight and thencooled down to 5° C. Aqueous HCl (12N, 10 mL) was added slowly to theflask, the flask was sealed again, and put into a 110° C. oil bathovernight. The resulting mixture was cooled to 5° C. and filtered. Thecollected solid was suspended in 100 mL of 2N aqueous HCl solution,stirred at 110° C. for 60 min, and filtered. The filtered solid waswashed with hexane and dried to provide compound II (1.88 g, 51% yield)as an off-white solid. HPLC purity: 97.1%. Mp: 211.0-212.7° C.; ¹H NMR(d₆-DMSO) δ 13.81 (broad s, 1H), 7.21 (broad s, 2H). ¹⁹F NMR (d₆-DMSO) δ−137.05.

Example 4b. Preparation of 4-Amino-6-bromo-3-chloro-5-fluoropicolinicacid

A mixture of compound V (3.92 g, 11.11 mmol), water (2 mL, 111.0 mmol,10 eq.) and anhydrous HBr in AcOH (5.7M, 78 mL, 444.6 mmol, 40 eq.) washeated at 110° C. for 18 h in a 500 mL sealed flask. The reactionmixture was then cooled to 0° C. and quenched with water (400 mL). Theresulting suspension was stirred for 30 min at 0° C., filtered and thecollected solid was washed with water (2×100 mL) and hexanes (3×100 mL)to provide compound II (2.08 g, 54% yield) as a beige solid. HPLCpurity: 96.5%. Mp: 211.3-212.5° C.; ¹H NMR (d₆-DMSO) δ 13.72 (broad s,1H), 7.16 (broad s, 2H). ¹⁹F NMR (d₆-DMSO) δ −130.28.

Example 4c. Preparation of 4-Amino-6-bromo-3-chloro-5-fluoropicolinicacid

In a 1 L Hastelloy C276 reactor, compound V (50 g, 0.142 mol., 1.0 mol.eq.) was suspended in water (8.93 g, 0.496 mol., 3.5 mol. eq.) and thenHBr (57.45 g, 0.71 mol., 5 mol. eq.) in acetic acid (116.6 g) was added.The reactor was heated to 110° C. with agitation and maintained at 110°C. for 8 h. The reactor was then cooled to 60° C. and filtered. The wetcake was washed with water (2×150 mL) and dried to provide compound II(42.6 g, 90% yield, 90% purity) as an off-white solid.

Example 4d. Preparation of 4-Amino-6-bromo-3-chloro-5-fluoropicolinicacid

In a 1 L Hastelloy C276 reactor, compound V (Z=CO₂-i-Pr; 50 g, 0.13mol., 1.0 mol. eq.) was suspended in water (8.25 g, 0.46 mol., 3.5 mol.eq.) and then HBr (53.0 g, 0.65 mol., 5 mol. eq.) in acetic acid (107.6g) solution was added. The reactor was heated to 110° C. with agitationand maintained at 110° C. for 8 h. The reactor was then cooled to 60° C.and filtered. The wet cake was washed with water (2×150 mL) and dried toprovide compound II (39.3 g, 90% yield) as an off-white solid. The HPLCpurity was determined to be 90%.

Example 4e. Preparation of 4-Amino-6-bromo-3-chloro-5-fluoropicolinicacid

In a 1 L Hastelloy C276 reactor, compound V (Z=CO₂Me, Y=H; 50 g, 0.142mol., 1.0 mol. eq.) was suspended in a mixture of water (8.93 g, 0.496mol., 3.5 mol. eq.) and a solution of HBr (57.45 g, 0.71 mol., 5 mol.eq.) in acetic acid (116.6 g). The reactor was heated to 110° C. withagitation, maintained at temperature for 8 h., and then cooled to 60° C.and filtered. The filtered wet cake was reslurried in 50 wt % aqueousmethanol (150 g) at 60° C. for 1 hr and filtered. The wet cake was driedto provide compound II (33.72 g, 87.6% yield) as an off-white solid. TheHPLC purity of the isolated product was determined to be 99.1%.

Example 4f. Preparation of 4-Amino-6-bromo-3-chloro-5-fluoropicolinicacid

In a 1 L Hastelloy C276 reactor, compound V (Z=CO₂iPr, Y=H; 50 g, 0.13mol., 1.0 mol. eq.) was suspended in a mixture of water (8.25 g, 0.46mol., 3.5 mol. eq.) and a solution of HBr (53.0 g, 0.65 mol., 5 mol.eq.) in acetic acid (107.6 g). The reactor was heated to 110° C. withagitation, maintained at temperature for 8 h., and then cooled to 60° C.and filtered. The filtered wet cake was reslurried in 50 wt % aqueousmethanol (150 g) at 60° C. for 1 hour and filtered. The wet cake wasdried to provide compound II (31.42 g, 88.2% yield) as an off-whitesolid. The HPLC purity of the isolated product was determined to be99.0%.

Example 4g. Preparation of 4-Amino-6-bromo-3-chloro-5-fluoropicolinicacid

Step 1:

Chemglass high pressure vessel (75 mL) equipped with magnetic stirrerwas charged with compound V (5.0 g, 14.18 mmol, 1 equiv) and HBr in AcOH(5.7M, 25 mL, 141.8 mmol, 10 equiv). The flask was sealed with PTFE capand heated at 50° C. for 24 h. The reaction mixture was cooled down to0° C. and quenched with water (50 mL). The suspension was stirred for 30min at rt, filtered, the solid was washed with water (2×30 mL) anddried.

Step 2:

To the crude mixture was added 40 mL of H₂SO₄/H₂O (2:1 v/v). The mixturewas stirred at 110° C. for 24 h, cooled to 0° C. and quenched with water(200 mL). The suspension was stirred for 30 min at room temperature,filtered. The solid was suspended in 200 mL of water, heated at 110° C.for 1 h, filtered hot suspension and dried to obtain compound II (2.67g, 70% yield, 2 steps). HPLC purity: 90.3%.

Example 4h. Preparation of 4-Amino-3,6-dichloro-5-fluoropicolinic acid

Step 1:

Compound V (2.5 g, 7.1 mmol, 1.0 eq.) was suspended in HCl in HAc (2M,fresh made in house and dry HCl bubbled through, 17.5 mL, 35 mmol, 5.0eq.) in a 75 mL glass sealed flask. The mixture was stirred at 90° C.oil bath for 19 h. The reaction mixture was cooled down to 5° C., openedthe flask carefully, poured into 60 mL of ice water, stirred for 30 min,filtered. The white solid was 4.5 g (wet) and used in the next reactionwithout further purification.

Step 2:

To the crude mixture was added 20 mL of H₂SO₄/H₂O (2:1 v/v). The mixturewas stirred at 110° C. for 24 h, cooled to 0° C. and quenched with water(100 mL). The suspension was stirred for 30 min at room temperature,filtered. The solid was suspended in 100 mL of water, heated at 110° C.for 1 h, filtered hot suspension and dried to obtain compound II (1.10g, 60% yield, 2 steps). HPLC purity: 91.4%.

Example 5a. Preparation of benzyl4-amino-6-bromo-3-chloro-5-fluoropicolinate

A 125 mL three-neck flask equipped with a magnetic stirrer, a cold watercondenser, a thermocouple and a nitrogen pad, was charged with4-amino-6-bromo-3-chloro-5-fluoropicolinic acid (5.0 g, 18.56 mmol) anddimethyl sulfoxide (20 mL). The mixture was stirred and powdered K₂CO₃(2.82 g, 20.41 mmol, 1.1 eq) was added in portions over 10 min (a mildextherm was observed with the temperature rising from 20 to 22.5° C.).After the mixture was stirred at ambient temperature for 30 min, benzylchloride (2.59 g, 20.41 mmol, 1.1 eq) was added in one portion. Theresulting mixture was stirred at ambient temperature for 15 min, 40° C.for 5 h, and 50° C. for 2 h. Then, the reaction mixture was cooled toambient temperature, water (75 mL) was added and the resulting mixturewas stirred for 30 min. The solid present was filtered, rinsed withwater (20 mL), suction-dried and dried in vacuum oven at 50° C.overnight to give the benzyl ester, 6.5 g (97% yield). ¹H-NMR (500HMz/CDCl₃) δ 7.44 (m, 2H), 7.35 (m, 3H), 5.40 (s, 2H), 4.98 (s, br, 2H).¹⁹F-NMR 6-129.16.

Example 5b. Preparation of benzyl4-amino-6-bromo-3-chloro-5-fluoropicolinate

A sample of 4-amino-6-bromo-3-chloro-5-fluoropicolinic acid (12.87 g, 82wt % purity as estimated by ¹H NMR, 39.17 mmol, containing 18 wt %(13.94 mmol) of phthalic acid) was dissolved in DMSO (100 mL) in a250-mL three-neck flask equipped with a magnetic stirrer, a cold watercondenser, a thermocouple and a nitrogen pad. Powdered K₂CO₃ (9.95 g, 72mmol) was added in portions over 10 min, resulting in a mild exothermicreaction with the temperature rising from 20 to 25° C. The mixture wasstirred at ambient temperature for 30 min, then benzyl bromide (8.00 g,46.8 mmol) was slowly added over 10 min while the temperature wasmaintained below 25° C. with a cold water bath. The resulting mixturewas stirred at ambient temperature for 4 h, then was poured into 300 mLof cold water. The resulting slurry was stirred for 15 min, filtered andrinsed with 100 mL of water. After suction drying, the crude product waswashed with hexane (100 mL), and dried at 45° C. in a vacuum overnightto provide the benzyl ester 13.40 g (95% yield).

Example 5c. Preparation of benzyl4-amino-6-bromo-3-chloro-5-fluoropicolinate

To a three-neck flask equipped with a stir bar, a heating mantle, and aDean-Stark trap with condenser, was added4-amino-6-bromo-3-chloro-5-fluoropicolinic acid (3.00 g, 11.13 mmol),benzyl alcohol (11.48 g, 10 eq), toluene, and p-toluenesulfonic acidmonohydrate (p-TSA, 212 mg, 0.1 eq). The mixture was heated at 80° C.,and slowly placed under a vacuum of 30 mm Hg in order to remove waterthat was generated in situ. After heating at 80° C. for 10 h, thereaction mixture was cooled to ambient temperature. Cyclohexane (50 mL)was added dropwise and the resulting slurry was stirred for 2 h, cooledto 10° C., filtered and the wet cake was rinsed with cyclohexane (10mL). The wet cake was then washed with water (20 mL), suction dried,rinsed with cyclohexane (5 mL), and dried at 45° C. under reducedpressure in a vacuum oven to provide 3.29 g (82.3% yield) of the benzylester.

Example 5d. Preparation of cyanomethyl4-amino-6-bromo-3-chloro-5-fluoropicolinate

A 125 mL round bottom flask equipped with a magnetic stir bar wascharged with 4-amino-6-bromo-3-bromo-5-fluoropicolinic acid (2.0 g, 7.42mmol) and acetone (30 mL). Bromoacetonitrile (1.034 mL, 14.84 mmol) wasadded followed by dropwise addition of triethylamine (4.14 mL, 29.7mmol). A white precipitate formed, and additional acetone (10 mL) wasadded. After 25.5 h, additional triethylamine (1.035 mL, 7.42 mmol),bromoacetonitrile (0.517 mL, 7.42 mmol) and acetone (10 mL) were added.The reaction mixture was stirred for an additional 22.5 h and then thevolatiles were removed under reduced pressure. The crude material wasre-suspended in EtOAc and washed with water. The layers were separatedand the organic layer was dried (Na₂SO₄), filtered, and concentratedunder reduced pressure to provide cyanomethyl4-amino-6-bromo-3-chloro-5-fluoropicolinate (1.365 g, 4.42 mmol) in 60%yield as an off-white solid. ¹H NMR (600 MHz, DMSO-d₆) δ 7.34 (s, 2H),5.27 (s, 2H). ¹⁹F NMR (564 MHz, DMSO-d₆): δ −127.73.

The compositions and methods of the claims are not limited in scope bythe specific compositions and methods described herein, which areintended as illustrations of a few aspects of the claims and anycompositions and methods that are functionally equivalent are intendedto fall within the scope of the claims. Various modifications of thecompositions and methods in addition to those shown and described hereinare intended to fall within the scope of the appended claims. Further,while only certain representative composition materials and method stepsdisclosed herein are specifically described, other combinations of thecomposition materials and method steps also are intended to fall withinthe scope of the appended claims, even if not specifically recited.Thus, a combination of steps, elements, components, or constituents maybe explicitly mentioned herein; however, other combinations of steps,elements, components, and constituents are included, even though notexplicitly stated. The term “comprising” and variations thereof as usedherein is used synonymously with the term “including” and variationsthereof and are open, non-limiting terms. Although the terms“comprising” and “including” have been used herein to describe variousembodiments, the terms “consisting essentially of” and “consisting of”can be used in place of “comprising” and “including” to provide for morespecific embodiments of the invention and are also disclosed.

What is claimed is:
 1. A compound of the formula:

wherein Z is COOR or CN, and R is a C₁-C₁₂ alkyl, C₆-C₁₂ arylalkyl, orH; and each Y substituent is independently selected from H, F, Cl, Br,I, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, ornitro, wherein n is 1, 2, 3, or
 4. 2. A method for preparing a compoundof Formula II, or an HCl of HBr salt thereof:

wherein X is Cl or Br, Z is COOR or CN, and R is H, C₁-C₁₂ alkyl, C₆-C₁₂arylalkyl, C₃-C₁₂ alkynyl, or C₁-C₃ alkyl substituted with CN;comprising the steps of: a) combining a compound of Formula III with aphthaloyl halide of Formula IIIa or a phthalic anhydride of FormulaIIIb, and, optionally a base,

wherein each Y substituent is independently selected from H, F, Cl, Br,I, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, ornitro, wherein n is 1, 2, 3, or 4; and W is Cl or Br; b) isolating acompound of Formula IV from step a);

c) combining an isolated compound of Formula IV from step b) with afluorinating compound or a fluorinating mixture of compounds; d)isolating a compound of Formula V from step c);

e) combining an isolated compound of Formula V from step d) with HCl orHBr and water; and f) isolating a compound of Formula II from step e).3. The method of claim 2 wherein step a) is preceded by step a′) whereinstep a′) comprises preparing a compound of Formula III, wherein Z isCOOR and R is C₁-C₁₂ alkyl, or C₆-C₁₂ arylalkyl, by contacting acompound of Formula III wherein R is H with an alcohol ROH, and an acidor acid forming compound.
 4. The method of claim 2, wherein step a)further comprises a solvent selected from acetonitrile (ACN), toluene,dimethylformamide (DMF), propionitrile, benzonitrile, THF, 2-methyl-THF,dioxane, cyclopentyl methyl ether (CPME), monoethyleneglycol ethers,diethyleneglycol ethers, monopropyleneglycol ethers, dipropyleneglycolethers, or methyl isobutyl ketone (MIBK), or mixtures thereof,preferably the solvent is ACN, toluene, DMF, CPME, or MIBK, morepreferably toluene.
 5. The method of claim 2, wherein a base in step a)is a trialkylamine compound, preferably triethylamine.
 6. The method ofany one of claims 2-5, wherein the combination of step a) is maintainedat a temperature from about 25° C. to about 100° C., preferably fromabout 25° C. to about 70° C.
 7. The method of claim 2 wherein afluorinating compound or a fluorinating mixture of compounds in step c)is potassium fluoride, cesium fluoride, tetramethylammonium fluoride,potassium fluoride/tetramethylammonium chloride, cesiumfluoride/tetramethylammminium chloride, or mixtures thereof, preferablypotassium fluoride.
 8. The method of claim 2, wherein step c) furthercomprises an aprotic solvent, preferably an aprotic solvent selectedfrom acetonitrile (ACN), propionitrile (PCN), benzonitrile (BCN),dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), sulfolane,dimethylacetamide (DMA), 1,1-dimethyl-2-imidizolidinone (DMI),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP),tetrahydrofuran (THF), 2-methyl-THF, dioxane, monoethyleneglycol ethers,diethyleneglycol ethers, monopropyleneglycol ethers, ordipropyleneglycol ethers, or mixtures thereof.
 9. The method of any oneof claims 2-8, wherein the combination of step c) is maintained at atemperature from about 15° C. to about 150° C., preferably from about25° C. to about 110° C.
 10. The method of any one of claims 2-9, whereinthe combination of step e) further comprises acetic acid.
 11. The methodof any one of claims 2-10, wherein step b) comprises isolating acompound of Formula IV by filtration or centrifugation, and/or step d)comprises isolating a compound of Formula V by filtration orcentrifugation, and/or step f) comprises isolating a compound of FormulaII by filtration or centrifugation.
 12. The method of any one of claims2-10, wherein a compound of Formula IV is not isolated in step b) and acombination from step a) is used directly in step c), and/or a compoundof Formula V is not isolated in step d) and a combination from step c)is used directly in step e).
 13. The method of claim 2, furthercomprising esterifying a compound of Formula II wherein Z=COOH bycombining a compound of Formula II wherein Z=COOH, from step f) with analcohol and an acid, or with an alkylating agent and a base, to providea compound of Formula VI,

wherein X=Cl or Br, and R¹ is C₁-C₁₂ alkyl, C₆-C₁₂ arylalkyl, C₃-C₁₂alkynyl, or C₁-C₃ alkyl substituted with CN.
 14. A compound of theformula:

wherein X=Br, Z is COOR, and R is H, C₂-C₁₂ alkyl, C₆-C₁₂ arylalkyl,C₃-C₁₂ alkynyl, or C₁-C₃ alkyl substituted with CN.
 15. A compound ofthe formula:

wherein X=Br, Z is COOR wherein R is H, Et, i-Pr, or CH₂-phenyl.